Regulation of lipogenesis will be studied and compared in diabetic and normal states. Initially the primary system of concern will be that of the rat liver. Several regulatory properties of the lipogenic enzymes (ATP-citrate lyase, acetyl-CoA carboxylase, and fatty acid synthetase) will be considered with respect to individual and cumulative effects on alteration of hepatic lipogenesis. Among those mechanisms which will be examined are: phosphorylation and dephosphorylation; interprotein associations (hetero-protein polymerization); synthetic and degradatory modulation of enzyme concentrations; and classical kinetic regulation in various states of altered enzyme integrity. Each mechanism of regulation will be considered in relation to alterations in plasma levels of the polypeptide hormones, insulin and glucagon, in order to offer more accurate postulations of the mechanisms of hormonal regulation of lipogenic flux in various tissues. The proposed studies will be carried out on purified enzymes, reconstituted complexes, and individual cells in culture. Utilizing techniques perfected in this laboratory, we propose to correlate the regulatory properties of the individual enzymes to the contribution of each aspect of regulation to total synthetic flux of acetate through the lipogenic pathway to form fatty acids. In turn, these regulatory properties will be correlated to the physiological normal and diabetic states.